1,2,3,6-tetrahydropyrimidine-2-one compounds and processes for makingthem

ABSTRACT

Tetrahydropyrimidine-2-one compounds which have been found to possess useful biological properties in that such compounds act through the central nervous system as depressants and/or stimulants. For use as medicaments, the novel tetrahydropyrimidine compounds are normally administered in the form of pharmaceutical compositions containing, as an active ingredient, at least one of the tetrahydropyrimidine compounds in association with a physiologically acceptable carrier. Illustrative of such compounds are 1-(2&#39;&#39;-hydroxyphenyl)-4-(3&#39;&#39;&#39;&#39;nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one which shows CNS depressant effects and 1-adamantyl-4-(3&#39;&#39;-nitrophenyl)-1,2,3,6tetrahydropyrimidine-2-one which shows CNS stimulant effects. The 1,2,3,6-tetrahydropyrimidine-2-one compounds having central nervous system activity are prepared by the reaction of a Beta aminoketone and an alkali metal cyanate which results in a tetrahydropyrimidine-2-one compound bearing a double bond in the 4,5 position.

United States Patent [191 Podesva et al.

[ 1 ,2,3,6-TETRAHYDROPYRIMIDINE-2-ONE COMPOUNDS AND PROCESSES FOR MAKINGTHEM [75] Inventors: Ctirad Podesva; Jose Maria D0 Nascimento, both ofMontreal, Quebec, Canada [73] Assignee: Delmar Chemicals Limited, VilleLa Salle, Quebec, Canada 22 Filed: Aug. 25, 1970 21 Appl. No.: 66,872

Mannich et al., Ber. 55, 365366, 369 (1922).

Primary Examiner-Donald G. Daus Assistant ExaminerR. V. Rush Attorney,Agent, or F irmFisher, Christen and Sabol, Virgil H. Marsh June 28, 1974571 ABSTRACT Tetrahydropyrimidine-2-one compounds which have been foundto possess useful biological properties in that such compounds actthrough the central nervous system as depressants and/or stimulants. Foruse as medicaments, the novel tetrahydropyrimidine compounds arenormally administered in the form of pharmaceutical compositionscontaining, as an active ingredient, at least one of thetetrahydropyrimidine compounds in association with a physiologicallyacceptable carrier. illustrative of such compounds are l-(2-hydroxyphenyl)-4-(-3"- nitrophenyl) ,2,3,6-tetrahydropyrimidine-2-onewhich shows CNS depressant effects and l-adamantyl-4-(3-nitrophenyl)-l,2,3,6-tetrahydropyrimidine-2-one which shows CNS stimulant effects.The- 1,2,3,6-tetrahydropyrimidine- 2-one compounds having centralnervous system activity are prepared by the. reaction of a B-aminoketoneand an alkali metal cyanate which results in atetrahydropyrimidine-Z-one compound bearing a double bond in the 4,5position.

' Claims, N0 Drawings pects provides l 1,2,3,6-TETRAHYDRPYRlMIDINE-2-ONECOMPOUNDS AND PROCESSES FOR MAKING.

THEM

BACKGROUND OF INVENTION This invention relates to novel biologicallyactive l,2,3,6 tetrahydropyrimidine-Z-onc compounds, to pharmaceuticalcompositions containing such compounds, and to a method of treatmentinvolving the administration of said compounds and compositions. Thisinvention is further concerned with processes for preparing said noveltetrahydropyrimidine-2-ones.

DETAILED DESCRIPTlON OF THE INVENTION A. Composition of Matter NovelCompounds This invention in one of its composition of matter asnovellR,-2-oxo-3H-4R -l,2,3,6-

tetrahydropyrimidine compounds in which each of R,

and R represents a hydrocarbon, a substituted hydrocarbon orheterocyclic radical, and functional derivatives thereof. Thesecompounds, therefore, may be represented by the following generalformula:

in which each of R, and R represents a hydrocarbon, a substitutedhydrocarbon or a heterocylic radical and functional derivatives thereof.

Preferred compounds within foregoing broad class are those representedby the following general formula:

T=O NH (Bah wherein R, has the same significance as in Formula Ihereinbefore, R represents a halogen atom or a nitro,

Formula I methyl, cyclohexylmethyl, or a cycloheptylmet hyl radical; acarbocyclic aryl radical such as a monocyclic or bicyclic carbocyclicaryl, for example, phenyl or a 2- naphthyl radical; or a carbocyclicaryl-lower aliphatic hydrocarbon radical, primarily monocycliccarbocyclic aryl-lower alkyl or bicycliccarbocyclic aryl-lower alkyl,for instance, ben'zyl, Z-phenyl-cthyl, or napthyl-2- methyl radical. Thevarious R, radicals may contain additional substitucnts; for instance,any aromatic, say, phenyl or naphthyl moiety, may be substituted bylower alkyl, for example methyl, or free or substituted, for example,O-alkyl or 0-acyl hydroxyl. I

These compounds of the invention are relatively high melting, usuallywhite, off-white Or yellow, crystalline solids which are substantiallyinsoluble in water. They are, however, soluble in polar solvents likeN,N-dimethylformamide and dimethyl sulfoxide. Examination of thecompounds produced according to the hereinafter described processesreveals, upon n.m. r. and infrared spectrographic analyses, spectraldata confirming the molecular structure hereinbefore set forth, such asthe location of the double bond between the 4 and 5 position of thering. For example, the infrared .spectrum of bon (alicyclic) radical inwhich the alicyclic portion may be saturated or may contain one or morethan one double bonds depending on the number of ring carbon atoms suchas monocyclic alkyl, bicyclic alkyl and tricyclic alkyl radical, forinstance n-cyclopropyl, cyclo-- butyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl,

such as a monocyclic alkyl-lower alkyl, for instance cybocyclicaliphatic-lower aliphatic hydrocarbon radical clopropylmethyl,cyclobutylmethyl, cyclopentylthe various compounds shows ahydrogen-bonded NH stretching band in the solid state atabout '3200 cm",along with a carbonyl C=O) stretching band at about 1640 cm The infraredspectra taken in chloroform solutions show the free NH stretching bandat about 3430 cm. The n.m.r. spectrum in deuterated chloroform revealsproton resonance signal at 5.61 (doublet integrating for 2 allylicprotons), at 4.8-r (triplet, integrating for l vinylic protonyand at 2.1r (singlet integrating for 1 NH proton). On addition of D 0 this lastsignal completely disappeared confirming the foregoing interpretation.The aforementioned physical char acteristics taken together with thenature of the starting materials and the mode of synthesis, positivelyconfirms the structure of thecompounds. v

, It has been found in accordance with the present invention that thenew l-R,-2 oxo-3.-H-4-R -l,2,3,6-tetrahydropyrimidine compounds possessuseful biologi-- cal properties in thatsuch compounds typically showpronounced central nervous system effects when administered to mice andrats, usually with a relatively low toxicity. Compounds exhibiting sucheffects may be of value-for therapeutic applications as potentialpsychotropic drugs. Usually the compounds show a marked depressiveeffect, often preceded by a brief stimulatory effect, on the centralnervous system when adrrii'nisteredto rats, indicative of ultimateanticonvulsant, relaxant, tranquilizing and similar clinical use inhuman beings, Such compounds therefore have a pharmacological profileshowing similarities both to certain substances which depress thecentral nervous system and to certain substances which stimulate thecentral nervous system. However, in some instances, notably when R, is atricyclic alkyl radical such as an adamantyl radical, the compounds havea significant stimulatory effect on the central nervous system whenadministered to mice and rats without any marked depressive effect,

indicative of ultimate antidepressant and'similar clinical use in humanbeings. While the compounds of this invention do differ among themselvesin the magnitude of their respective activities, they are generallycharac-' terised by the type of activity indicated in the foregoing.

Particularly pronounced CNS depressive activity, usually with anegligible degree of side effects and a low degree of toxicity are foundin the lR,-2-oxo3-H-4- R 1 ,2,3,6-tetrahydropyrimidine compounds of theformula:

tetrahydropyrimidine-2-one; 1-(2'-hydroxyphenyl)-4- (3 "-bromophenyl -l,2,3,6-tetrahydropyrimidine- 2-one; l-( 2-hydroxyphenyl )-4-( 3-chlo'rophenyl- 1,2,3 ,6-tetrahydropyrimidine-2-one; and l-(2'-hydroxyphenyl )-4-( 3 -idophenyl l ,2,3,6-tetrahydropyrimidine-2-one.

An additional group of compounds of this series which also show good CNSdepressive activity usually with a negligible degree of side effects anda low degree of toxicity are the compounds of the formula:

.Ffl 'li i y in which R represents a straight or branch-chain aliphatichydrocarbon radical, especially an alkyl or alke nyl radical, or amonocyclic 'aryl such as phenyl radical an essential active ingredientat least one active compound of Formula I in association with apharmaceuti 4 rahydropyrimidine-Z-one; 1 2 -propoxyphenyl )-4- (3"-chlorophenyU-l ,2,3,6-tetrahydropyrimidine- 2-one; 1-(2-acetoxyphenyl)-4-( 3 '-iodophenyl 1,2,3 ,6-tetrahydropyrimidine-2-one;l-( 2- propoxyphenyl )-4-( 3 "iodophenyl )-l,2,3,6-tetrahydropyrimidine-Z-one; l-(2-acetoxyphenyl)-4-(3"-trifluoromethylphenyl l ,2,3,6-tetrahydropyrimidine- 2-one.

A group of compounds of this serieswhich typically display pronouncedstimulant effects on the CNS when administered to mice and rats, usuallywith a negligible degree of side effects and a low degree of toxicity,are compounds of the formula:

Formula V wherein Z represents a substituted or unsubstituted tricyclicalkyl radical and substituent X, preferably located in a meta position,represents a nitro group or a halogen atom. Representative of this groupof compounds is l-adamantyl-4-(3-nitrophenyl)-l,2,3.6-tetrahydropyrimidine-Z-one. This particular compound is alsofound to antagonize markedly the toxic effects of amphetamineadministered to mice.

B. Composition of Matter Pharmaceutical Compositions I The presentinvention further provides in another of its aspects a pharmaceuticalcomposition comprising as cally acceptable carrier therefor.

The compositions of the present invention are preferably administeredorally, rectally or parenterally. Ad-

vantageously, the composition is in a dosage unit form appropriate tothe desired mode of administration; For

example, the dosage unit may be a tablet, capsule, pill, powder, packet,granule, wafer, elixir, suppository, or' a measured quantity of asuspension, solution, a syrup or segregated multiples of the foregoing.The term dosage unit form as used in the specification and claims refersto physically discrete units suitable as unitary dosages for humansubjects and animals, each unit containing a predetermined quantity ofactive material cal- I culated to produce the desired therapeutic effectin adand X represents a nitro or trifluoroalkyl group or a halogen atom.Preferably ring substituent Xis located in a meta position.Representative of this group of com]- pounds are: 1-(2-acetoxyphenyl)-4-( 3' '-nitrophenyll,2,3,6-tetrahydropyrimidine-2-one; propoxyphenyl )-4-( 3 '-nitrophenyll ,2,3 ,6-tetrahydropyrimidine-2-one; l-(2-n-butyroxyphenyl)-4-( 3"-nitrophenyl )-l ,2,3,6-tetrahydropyrimidine-2-one; l-(Z-undecyleneoxyphenyl)-4-( 3 '-nitrophenyl )-1 ,2,3,6-tetrahydropyrimidine-2-one; l-2'-benzoxyphenyl)-4- (3 '-nitrophenyl l,2,3 ,6-tetrahydropyrimidine-Z-one; l( 2 '-acetoxyphenyl )-4-( 3-bromophenyl l ,2,3 ,6- tetrahydropyrimidine-Z-one; l-( 2'-propoxyphenyl)-4- 3 "-bromophenyU- l ,2,3,6-tetrahydropyrimidine-2-one;

mixture, or otherwise in association, with a pharmaceutical carrier, thequantity of the active ingredient being; such that one or more units arenormally required fora single. therapeutic administration or that, inthe case of severable units such as scored tablets, at least onefraction such as a half or a quarter of a severable unit is required fora single therapeutic administration.

Usually the compositions of this invention contain the activeingredientin an amount of at least 0.5% by weight based on'the total weight of thecomposition and not more than by weight. Conveniently, the compositionsof the invention when in dosage unit form contain 0.5 mg. to mg., andmore conveniently from 5 mg. to 50 mg., of the active ingredient ofFormula l.

mally consist of at least one compound of Formula 1,

advantageously a compound of Formulall, and more advantageously acompound from the preferred groups defined by Formulae III, IV, and V,admixed with a carrier, or diluted by a carrier, or enclosed orencapsulated by a carrier in the form of a capsule,-sachet, catchet,paper or other container. A carrier which serves as a vehicle, excipientor diluent medium for the therapeutically active ingredient may be asolid, semisolid or a sterile liquid.

Some examples of the carriers which may be employed in thepahrmaceutical compositions of the invention arelactose, dextrose,sorbitol, mannitol, starches such as wheat, corn, orpotatoe starch, gumacacia, calcium phosphate, liquid paraffin, cocoa butter, oil oftheobroma, alginates, tragacanth, gelatin,

syrup B.P., methyl cellulose, polyoxethylene sorbitan monolaurate, andmethyl and propyl hydroxybenzoates. In the case of tablets, a lubricantmay beincorporated to prevent sticking and binding of the powderedingredients in the dies and on the punch of the tabletting machine. Forsuch purpose, there may be employed, for example, talc, aluminum,magnesium or calcium stearates or polyethylene. glycols (Carbowaxes) ofsuitable molecular weight.

Thepharmaceutical compositions of this invention may contain, inaddition to the active l-R -2-oxo-3-H- 4-R -l,2,3,6-tetrahydropyrimidine ingredient, one of more otherphysiologically active ingredients which elicit desirable complementaryeffects.

C. Method of Treatment As indicated hereinbefore, it has been found inac- I cordance with the present invention that the compounds of Formula'l possess useful biological properties in that such compounds possessthe inherent applied use characteristics of exerting a depressant and/orstimulant effect on the central nervous system. Compounds possessingsuch activity may have very valuable therapeutic utility as potentialmedicaments in the form of pharmaceutical compositions in elicitingadvantageous central nervous system effects when administered to humansand-animals. Accordingly, this invention in its method-of-use aspectsprovides a method of eliciting depressant and/or stimulant centralnervous system effects, including humans and animals, by administering atherapeutically effective dose of one or more of the active compounds ofFormula 1 (preferably a compound of Formula ll, and more preferably acom- 6 symptom being treated, the age, health and weight of therecipient, the extent of the symptom, kind of concurrent treatment, ifany, and the precise nature of the effect desired. In practise, basedupon standard pharmacological animal studies, particularly in mice, ithas been found that the administration of doses of about 1 to 100 mg. ofthe active compounds of this invention per kg. of animal body weightwill usually elicit the aforementioned CNS effect(s) normally withoutproducing any marked side effects.

D. Process The novel compounds of this invention may be prepared byreacting a ,B-amino-ketone compound of the following formula:

wherein R and R have the same significance as hereinbefore with acyanate, especially an alkali metal cyanate such, for example, aspotassium or sodium cyana'te. Preferably the B-amino-ketone is reactedwith the cyanate in about stoichiometric amounts. Preferably, thereaction is conducted under acidic conditions. Hence, it is oftenconvenientto use the B-amino-ketone in the form of an acid additionsaltsuch, for example, as a hydrohalide salt thereof. Conveniently thereaction is carried out in the presence of an acidic solvent, forexample, in an acid such asacetic acid, formic acid or the like. Usuallythe reaction is effected under relatively mild conditions atatemperature of between ambient temperature and 100C, preferably between40 and C. a

That the B-amino-ketone compound andthe cyanate should condense togetherwith formation of a tetrahydropyrimidine nucleus containing acarbon-carbon double bond atthe 4-5 position in the ring is surprisingand unexpected since the skilled chemist would have expected the finalcompounds to contain a C=N linkage. At the present tim'e,-on the basisof spectral data available to us, it is believed that the reactionproceeds through the initial formation of a substituted urea as anintermediate which cyclises spontaneously, with the elimination ofwater, by nucleophilic attack of the primary urea nitrogen on theelectron deficient carbonyl carbon atom followed byan internalrearrangement with migration of the double bond from the 3-4 to the 4-5position in the tetrahydropyrimidine ring. This sequence of reactions isindicated below:

pound of Formula III, IV or V). The dosage administered will bedependent upon such factors as the CNS NH: (R and R; as before, and Malkell metal) urea intermediate v1 0 /N Rearrangement CH Y a'i-N $42,

FormulaI \C l A transient unstable intermediat In the above process itis of advantage to use as starting compounds those which lead to theformation of FQUQQE Y1.

the tetrahydropyrimidines mentioned hereinbefore as being especiallyvaluable. Illustrating this generally applicable process is thepreparation of a l-o-hydroxyphenyl-2-oxo-4-m-Rphenyl-l,2,3,6,tetrahydropyrimidine, such a compound may be obtained by:f

i. dissolving a corresponding B-anilino-m-R3- propiophenone in the formof an acid addition, typically hydrogen halide, salt in an acid,especially acetic acid, advantageously at a temperature of about 40 toabout 70C, say about 60C;

ii. adding a stoichiometric amount of an alkali cyanate, such aspotassium cyanate, to the resulting solution whereupon an exothermicreaction takes place resulting in ring closure with formation of thepyrimidine nucleus. During the course of this reaction, for each mole of'reaction product there is formed a mole of an alkali metal halide;

If desired, the tetrahydropyrimidine compound soobtained may betransformed according to known methods into functional derivatives such,for example, as -alkyl or O-acyl derivatives.

Formation of the 0-acyl derivatives may be accomplished by reacting acorresponding free phenolic hy-, droxy compound with the appropriatecarboxylic acid or a'functional derivative thereof such as a halide,for, example, a chloride or an anhydride. The esterification reactionmay be carried out according to known conditions, for example, in theabsence or presence of a condensing agent such as a liquid organic base,for example, triethylamine, pyridine'or collidine, particularly if ananhydride, for example, acetic anhydride is used, or trifluoroaceticanhydride, particularly if a free acid, say, acetic, butyric, valeric orcyclopropylcarboxylic acid is used as the esterifying agent. Liquidbasic condensation reagents, such as, for example, pyridine orcollidine,-may simultaneously serve as solvents. A liquid-acylationreagent, such as, for example, acetic'acid anhydride may be used withoutan additional solvent.

The compounds prepared according to the foregoing proccdures are, ingeneral, crystalline solids that may be recovered by filtration or bycentrifuging and purifled by recrystallization from an inert organicsolvent or solvent mixture such as, for example, methanol, eth

anol, I acetone, ethyl' acetate, acetone-hexane,N,N'-dimethylformamide,. or by chromatography using an absorbent such assilica gel or magnesium silicate.

The B-amino-ketone starting compounds of Formula VI used'in theabove-described processes are known, or if new, may be obtainedaccording to procedures used for the manufacture of known compounds, asillustrated in the following Examples.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS ,The following Examplesare provided by way of affording a more comprehensive understanding ofvarious aspects of this invention. In these Examples, all melting pointswere determined by the capillary tube method.

drochloride had completely dissolved. 1.5 G. of oaminophenol were addedand the solution refluxed for 0.5 hours, then set aside to cool. Thereaction product crystallized out of solution to yield 1.6 G. of thedesired [3-(o hydroxyanilino)-m-nitropropiophenone which had a meltingpoint of 107 to 109C.

Part B B-(o-Hydroxyanilino)-m-nitropriopiophenone hydrochloride The freebase obtained by the procedure of Part A was dissolved in 5 ml. ethanoland concentrated hydrochloric acid added until the solution was acidicto litmus. Evaporation of the solvent in vacuo, and crystallization frommethanol-acetone yielded 1.6 G. of the desiredB-(o-hydroxyanilino-m-nitropropiophenone) hydrochloride which had amelting point of 172 to 173C.

Part C 1-(2'l-lydroxyphenyl)-4-(3"-nitrophcnyl)-l,2,3,6-tetrahydropy'rimidine-Z-onenitropropiophenone hydrochloride obtained by the procedure of Part Bwere dissolved in 10 ml. acetic acid at 60C. 2 G. of potassium cyanatewere added and an exothermic reaction was, noted. After cooling to roomum ma) C(92) v Calculated: 61.73 4.58 13.36 m m a i Found: 6|.53 4.2013.49

. EXAMPLE 2 Part A B-(o-Hydroxyanilino)-propiophenone v 4 G. ofB-diethylaminop ropiophenone hydrochloride were dissolved in mllof 50%aqueous ethanol, and the mixture refluxed with stirring until thehydrochloride had completely dissolved. 2. 1- G. of o aminophenol wereadded and the solution refluxed for'0 .5 hours, then set aside to cool.The reaction product crystallized out of solution to yield 3 G. of thedesired ,B-(o-hydroxyanilino)-propiophenone 116 to 120C. Part B whichhad a melting point of B-( o-I-Iydroxyanilino )-pr'opiophenone hydrochloride The free base obtained by the procedure of Part A wastransformed into the hydrochloride salt by reaction of an ethanolicsolution of the base with concentrated hydrochloric acid following theprocedure of Part B of the foregoing Example. This hydrochloride salthad a melting point of to 162C. Part C l-( 2'-Hydroxyphenyl)-4-phenyll,2.3 ,6-tetrahydropyrimidine-Z-one 4 G. ofB-(hydroxyanilino)-propiophenone hydrochloride obtained by the procedureof Part B were .dis-

solved in 50 ml. of acetic acid at 60C. 3.4 G. of potassium cyanate wereadded and the exothermic reaction and then isolation of the desiredcompound conducted C(7r) H( W Calculated: 72.44 5.33 10.78 C16 H14 N2 02Found: 72.71 5.30 10.52

EXAMPLE 3 Part A B-(o-Hydroxyanilino)-p-nitropropiophenone 3 G. ofB-diethylamino-p-nitropropiophenone hydrochloride were added to 50 ml.of 50% aqueous ethanol and the mixture refluxed with stirring until thehydrochloride had dissolved completely. 1.4 G. of oaminophenol wereaddedand the solution refluxed for 0.5 hours then set aside to cool. Thereaction product crystallized out of solution to yield the desiredB-(ohydroxyanilino)-p-nitropropiophenone, which had a' melting point of151 to 152C. Part B B-(o-l-lydroxyanilino)-p-nitropropiophenone chlorideI hydro- The free base prepared by the procedure of Part A wastransformed into the corresponding hydrochloride salt by reaction of anethanolic solution of the base with concentrated hydrochloric acidfollowing the procedure of Part B of Example 1. This hydrochloride salthad a melting point of 161 to 163C. Part Cl-(2'-1-1ydroxyphenyl)-4-(4'-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-Z-onev 1.5 G. of B-(o-hydroxyanilino)-pnitropropiophenone hydrochlorideobtained by the procedure of Part B were dissolved in 10 ml. of aceticacid at 60C. 2 G. of potassium cyanate were added and the reaction andthen the isolation of the desired compound conducted following exactlythe same procedure as set forth in Example 1, Part C. The 1-(2-hydroxyphenyl )-4-(4 -nitrophenyl)-1,2,3,6-tetrahydropyrimidine-Z-one soobtained was recrystallized from a mixture of N,N-dimethylformamide andethyl acetate; it had a melting point of 219 to 220C. Analysis of theproduct yielded the following results:

B-(o-Methoxyanilino)-m-nitro propiophenone.

3 G. of B-dimethylamino-m-nitropropiophenone hy-' drochloride were addedto a mixture of 30 ml. ethanol and 30 ml. water which was stirred untilall the phe-' none had dissolved. 1.4 G. of o-anisidine were added andthe solution refluxed. for 0.5 hours then set aside to cool. Thereaction product crystallized out of solution to yield 3 g. of thedesired B-(o-methoxyanilino)-pnitropropiophenone, which had a meltingpoint of 84 to 86C.

Part B I B-(o-Methoxyanilino)-m-nitropropiophenone hydrochloride Thefree base prepared by the procedure of Part A 5 was transformed into thecorresponding hydrochloride salt by reaction of an ethanolic solution ofthe base (3 G. in 5 ml.) with concentrated hydrochloric acid followingthe procedure of Part B of Example 1. Part C l-(2-Meth'oxyphenyl)-4-( 3-nitropheny1)-1,2,3,6-tetrahydropyrimidine-Z-one TheB-(o-methoxyanilino)-m-nitropropiophenone hydrochloride obtained by theprocedure of Part B were dissolved in 20 ml. of acetic acid at ambienttemperature (025C). 3 G. of potassium cyanate were added with stirringand an exothermic reaction was no-,

ted. After cooling' to around ambient temperature, water was added untila precipitate began to form. The aqueous solution was extracted 3 timeswith mls. of ethyl acetate, and the organic extracts combined thenwashed successively with 10% aqueous sodium hydroxide, water, 10%aqueous hydrochloric acid, water, dried over sodium sulphate, filteredand evaporated to dryness. The residue was recrystallized from anethanol-ether mixture to give the desired l-(2'- methoxypheny1)-4-(3-nitrophenyl)-1,2.3 .6-tetrahydropyrimidine-Z-one. which had a meltingpoint of 247 to 249C. Analysis of the product yielded the followingresults: I 5

C(71) H('/1) NW1) Found: 62.91 4.39 12.82 CIT H 04 N3 Calculated: 62.764.64 12.91

5 EXAMPLE 5 Part A B-(o-Carboxyanilino)-m-nitropropiophenone 5 G. ofB-diethylamino-m-nitropropiophenone hydrochloride were added to 60 m1.of 50% aqueous ethanol and stirring continued until all the phenone haddissolved: 2.5 G. of anthranilic acid were added and the solutionrefluxed for 0.5 hours then set aside to cool. The reaction productcrystallized out of solution to yield B-(o-carboxyanilino)'-mnitropropiophenone, which had a melting point of 165 to 169C. Part B g,8-(o-Carboxyanilino)-m-nitropropiophenone The free base prepared by theprocedure of Part A was transformed-into the corresponding hydrochloridesalt by suspension in concentratedhydrochloric acid. This hydrochloridesalt had a melting point of 156C of potassium cyanate were added and. asusual, anexothermic reaction was noted; this was accompanied by thecomplete solvation of the hydrochloride. The desired 1-( 2-carboxyphenyl)-4-( 3 -nitrophenyl .1,2,3,6-tetrahydropyrimidine-2-one so-formedwasisolated following exactly the same procedure as set forth in Example 1,Part C. The compound was recrystallized from a mixture ofN,N-dimethylformamide and acetone; it had a melting point of 247 to250C. Analysis of the product yielded the following results:

'cwo 11w.) N(7() Found: 60.01 4.04 12.15 C11 H13 a Calculated: 60.173.86 12.38

EXAMPLE 6 Part A filtration. This compound had a melting point of 107 to109C. Part B B-(o-Hydroxyanilino)-m-bromopropiophenone hydrochloride 21G. of B-diethylamino-m bromopropiophenone prepared by the procedure ofPart A were added to 100 ml. of 50% aqueous ethanol and stirringcontinued until all the phenone had dissolved. 6.1 G. of o-aminophenolwere added and the solution refluxed for 0.5 hours then set aside tocool. Thereafter, the solution was extracted twice with 50 m1. ethylacetate, the organic extracts combined and an excess mls.) concentratedhydrochloric acid added to the organic phase. The solution was set asideand after a short time B-(ohydroxyanilino)-m-bromopropiophenonehydrochloride crystallized out. This compound was recrystallized from amethanol-acetone mixture; it had a melting point of 168 to 171C. Part Cl-(2 '-Hydroxyphenyl)-4-( 3 -bromophenyl l ,2.3,6-tetrahydropyrimidine2-onc 6 G. ofB-(o-hydroxyanilino)-mbromopropiophenone hydrochloride prepared by theprocedure of Part B were dissolved in 50 ml. of acetic acid at 60C. 3 G.of potassium cyanate were added and, as usual, an exothermic reactionwas noted. After coolingv to room temperature, 100 mls. water wereadded, and the bromophenyl )-l ,2,3 ,6-tetrahydropyrimidine-Z-oneprecipitated out of solution. The suspension was extracted twice with 20mls. ethyl acetate. The organic extracts were combined and washedsuccessively with 10% aqueous sodium hydroxide, 10% aqueous hydrochloricacid and water then dried over sodium sulfate and concentrated byheating in vacuo. The concentrated solution was set aside to cool, whencrystals of the desired l-(2'-hydroxyphenyl)-4-(3"- bromophenyl)- 1,2,3,6-tetrahydropyrimidine-2-one separated out and were collected byfiltration. The product had a melting point of 180 to 181C., andanalysis thereof yielded the following results:

C(7r) H1 1 811 Found 55.61 3.70 7.96 23.00 is ia z' a Calculated 55.663.79 8.11 23.15

'EXAMPLE 7 Part A B-Diethylamino-m-chloropropiophenone hydrochlorideThis compound was prepared by a Mannich reaction in which a mixture of17 G. of m-chloroacetophenone, 15 G. of diethylamine hydrochloride and18 ml. of 37% aqueous formaldehyde acidified with a few drops ofconcentrated hydrochloric acid was heated under reflux for 2 hours.After cooling to room temperature, 18 g. of,B-diethylamino-m-chloropropiophenone hydrochloride were collected byfiltration. This compound had a melting point of to 123C.

Part B /3-(o-Hydroxyanilino)-n1-chloropropiophenone hydrochloride 16 G.of[3-diethylamino-m-ehloropropiophenone hydrochloride prepared by theprocedure of Part A were added to 100 ml. of 50% aqueous ethanol andstirring continued until all the phenone had dissolved. 6.3 G. ofo-aminophenol were added and the solution refluxed for 0.5 hours, thenset aside to cool. Thereafter, the solution was extracted twice with 50ml. ethyl acetate. the organic extracts combined and an excess 10-mls.)concentrated hydrochloric acid added to the organic phase. The solutionwas set aside and after a short time 15 G.B-(o-hydroxyanilino)-m-chloropropiophenone hydrochloride crystallizedout. This'compound was recrystallized from a methanol-acetone mixture;it had a melting point of 161 to 163C.

Part C and concentrated by heating in vacuo. The concentrated solutionwas set aside to cool, when crystals of the desired 1-( 2 -hydroxyphenyl)-4-( 3 chlorophenyl)-1,2,3,6-tetrahydropyrimidine-2-one separated outand were collected by filtration. The product had a melting point of 173to 175C, and analysis thereof yielded the following results:

C(7:) CW7!) Found 64.07 4.59 9.39 11.82 IG U Z Z Calculated 63.89 4.359.31 11.78

EXAMPLE 8 PartA B-Dimethylamino-m-iodopropiophenone hydrochloride Thiscompound was prepared by a Mannich reaction in which a mixture of 24 G.of m-iodoacetophenone, 6.4 G. of dimethylamine hydrochloride and 3.2 g.of paraformaldehyde dissolved in 20 ml. acetic acid was heated underreflux for two hours, then concentrated in vacuo. After cooling to roomtemperature, the reaction mixture was diluted with acetone and 23 g. ofcrystalline B-dimethylamino-m-iodopropiophenone hydrochloride collectedby filtration. This compound recrystallized from a methanol-acetonemixture had a melting point of 212 to 214C. Part B,B-(o-Hydroxyanilino)-m-iodopropiophenone hydrochloride 6.5 G. ofB-dimethylamino-m-iodopropiophenone hydrochloride prepared by theprocedure of Part A were added to 60 ml. of an ethanol-water mixture 1:1and stirring continued until all the phenone had dissolved. 2 G. ofo-aminophenol were added and the solution refluxed for 0.5 hours, thenset aside to cool. Thereafter, the solution was extracted twice with ml.ethyl acetate, the organic extracts combined and an excess (3 mls.)concentrated hydrochloric acid added to the organic phase. The solutionwas set aside and after a short time 3 g.B-(o-hydroxyanilino)-miodopropiophenone hydrochloride, crystallized out.This compound, recrystallized from a methanolacetone mixture, had amelting point of 174 to 176C. Part-C l-(2'-hydroxyphenyl )-4-( 3-iodophenyl)- l ,2.3,6-tetrahydropyrimidine-2-one ofB-(o-hydroxyanilino)-mbromopropiophenone hydrochloride prepared by theprocedure of Part B were dissolved in ml. of acetic acid at 60C. 1 G. ofpotassium cyanate was added and,

Part B B-(o-Hydroxyanilino)-m-trifluoromethylpropiophenone hydrochloride2.8 G. of B-dimethylamino-m-trifluoromethylpropiophenone hydrochlorideprepared by the procedure of Part A were added to 20 ml. ofethanol-water mixture (1:1) and stirring continued until all the phenonehad dissolved. 1 G. of o-ar'ninophenol was added and the solutionrefluxed for 0.5 hours, then set aside to cool. Thereafter, the solutionwas extracted twice with 10 ml. ethyl acetate, the organic extractscombined and an excess (3 mls.) concentrated hydrochloric acid added tothe organic phase. The solution was set aside and after a short time 1.6B-(o-hydroxyanilino-mtrifluoromethylpropiophenone hydrochloridecrystallized out. This compound, recrystallized from a methanol-acetatemixture, had a melting point of 172 to 175C. Part C 1-( 2'-Hydroxyphenyl)-4-( 3 -trifluoromethylphenyl 1,2,3,6-tetrahydropyrimidine-Z-one 7 G.of B-(o-hydroxyanilino)-m-trifluoromethylpropiophenone hydrochlorideprepared by the proceas usual, an exothermic reaction was noted. Aftercooling to room temperature, mls. water were added, and the1-(2'-hydroxyphenyl)-4-(3-iodophenyl)-l,2,3,6-tetrahydropyrimidine-2-one'precipitated out of solution. Thesuspension was extracted twice with 10 mls. ethyl acetate. The organicextracts were combined and washed successively with 10% aqueous sodiumhydroxide, 10% aqueous hydrochloric acid and water then dried oversodium sulfate and concentrated by heating in vacuo. The concentratedsolution was set aside to cool, when crystals of the desired 1-(2-hydroxyphenyl)-4-(3"-iodopheny1)-1 ,2 ,3 ,6-tetrahydropyrimidine-2 oneseparated out and wefe c cfll ected by filtration. The compoundrecrystallized from ethyl acetate had a melting point of 181 to 183C.Analysis of this product yielded the following results:

cum 4( 0 N(7r) Found 49.17 3.69 6.80 32.16 ua m 2 L' Calculated 48.993.34 7.14 32.36

EXAMPLE 9 Part A ,8-Dimethylamino-m-trifluoromethylpropiophenonehydrochloride v This compound was prepared by a Mannich reaction inwhich a mixture of 17 g. of' mtrifluoromethylacetophenone, 6.5 g. ofdimethylamine hydrochloride and 4.2 g. of paraformaldehyde .dissolved in20 ml. acetic acid was heated under reflux for 2 hours, thenconcentrated in vacuo. After cooling to room temperature, the reactionmixture was diluted with acetone and 20 g. of crystalline,B-dimethylaminom-trifluoromethylpropiophenone collected by filtration.This compound recrystallized from a methanolacetate mixture had amelting point of 148 to 150C.

dure of Part B were dissolved in 20 ml. of acetic acid at 60C. 3 G. ofpotassium cyanate were added and, as usual, an exothermic reaction wasnoted. After cooling to room temperature, 40 mls. water were added, andthe l-(2'-hydroxyphenyl)-4-(3"- trifluoromethylphenyl l ,2,3,6-tetrahydropyrimidine- 2-one precipitated out of solution. Thesuspension was extracted twice with 20 mls. ethyl acetate. .The organicextracts were combined and washed successively with 10% aqueous sodiumhydroxide, 10% aqueous hydrochloric acid and water then dried oversodium sulfate and concentrated by heating in vacuo. The concentratedsolution was set aside to cool, when crystals the desired l-( 2'-hydroxyphenyl)-4-( 3 -trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-2-one separated out and were collected byfiltration. The compound recrystallized from ethyl acetate had a meltingpoint of 182 to 183C. Analysis of the product yielded the followingresults:

CV HU W Found: 60.48 4.07 8.60 CIT m 2 2 Calculated: 61.07 3.92 8.38

EXAMPLE 10 1-(2-Hydroxyphenyl)-4-(3"-cyanophenyl)-1,2,3,6-

' tetrahydropyrimidine-2-one 1.5 G. of1-(2-hydroxyphenyl)-4-(3"-iodophenyl)-1,2,3,6-tetrahydropyrimidine-2-one prepared by the procedure of Part Cof Example 8 were refluxed for 6 hours in 20 ml. N,N-'dimethylformamidecontaining 1 g. of anhydrous cuprous cyanide. The solution was set asideto cool to ambient temperature, then poured into 20 ml. saturated ferricchloride solution. The reaction mixture was extracted with ethyl acetateand the organic extracts washed, in turn, with 10% aqueous hydrochloricacid, water, 10% aqueous sodium carbonate and water. On evaporation todryness, 600 mg. of a residue were obtained which was purified by columnchromatography using a silica-gel adsorbent. The fraction eluted with 2%ethyl acetate-methanol mixture crystallized to give the desired1-(2'-hydroxyphenyl)-4-(3"-cyanophenyl)-1,2,3,6-tetrahydropyrimidine-2-one in good yield; it had amelting point of 265 to 267C.

15 Analysis of this product yielded the following results:

H(7) N Found: 70.34 4.34 14.60 C11 m J 2 Calculated: 70.09 4.49 14.42

EXAMPLE 11 Part A ,8-Adamantanylamino-m-propiophenone hydrochloride Amixture of 4.5 g. of m-nitroacetophcnone, 4.5 ml. of 37% aqueousformaldehyde and g. 1-

aminoadamantane hydrochloride acidified with a few drops concentratedhydrochloric acid was heated under reflux for 2 hours. After cooling toroom temperature, the reaction mixture was diluted with acetone and thedesired crystalline B-adamantanyl-m-nitropropiophenone hydrochloridewhich separated out collected by filtration. This compound had a meltingpoint 7 of 182 to 184C. Part B l-Adamantyl-4-( 3 '-nitropheny1 1,2,3,6-tetrahydropyrimidine-2-one. I

4.5 G. of B-adamantanylamino-mnitropropiophenone hydrochloride preparedby the procedure of Part A were suspended in 20 ml. of acetic acid andthe suspension heated under reflux until the hydrochloride went intosolution. 1.5 G. of potassium cyanate were added and, as usual, anexothermic reaction was noted. After cooling to room temperature 40 mls.water were added and the precipitated 1- adamantyl-4-( 3 "nitrophenyl)-l ,2,3 ,6-tetrahydropyrimidine-2-oric so-formed collected by filtration.This precipitate was extracted with hot methanol, and the insolublefraction crystallized from N,N-dimethylformamide to yield 0.5 of thedesired l-adamantyl-4- (3 '-nitrophenyl )-1 ,2,3,6-tetrahydropyriinidine-Z-one with a melting point of 225 to 227C.Analysis of this product yielded the following results:

C(71) H(7r) NV/r) Found: 67.42 6.62 12.00 C211 H211 N3 03 Calculated:67.97 6.56 1 1.89

EXAMPLE 12 Part A B-Cyclohexylamino-m-nitropropiophenone hydrochloride Amixture of 8 g. of m-nitroacetophenone, 4 ml. of 37% aqeuousformaldehyde and 7 g. cyclohexylamine hydrochloride acidified with a fewdrops concentrated hydrochloric acid was heated under reflux for 2hours. After cooling to room temperature, the reaction mixture wasdiluted with acetone and 10 g. of the desired crystallineB-cyclohexylamino-m-nitropropiophenone hydrochloride which separated outcollected by filtration. This compound had a melting point of 182 to185C.

Part B 1-Cyc1ohexyl-4-( 3'-nitropheny1)-1,2,3,6-tetrahydropyrimidine-2-one.

4 G. of B-cyclohexylamino-m-nitropropiophenone hydrochloride prepared bythe procedure of Part A were suspended in ml. of acetic acid and thesuspension heated under reflux until the hydrochloride went C( /r) H071)Nl Found: 63,72 6.50 13.82 u; H19 N11 :1

Calculated: 63177 6.36 13.94

EXAMPLE l3 Part A B-n-Butylamino-m-nitropropiophenone hydrochloride Amixture of 10 g. of m-nitroacetophenone, 7 ml. of 37% aqueousformaldehyde and 9 g. n-butylamine hydrochloride acidified with a fewdrops concentrated hydrochloric acid was heated under reflux for 2hours. After cooling to room temperatureQthe reaction mixture wasdiluted with acetone and the desired crystallineB-n-butylamino-m-nitropropiophenone hydrochloride which separated outwas collected by filtration. This compound had a melting point of to148C. Part B l-n-Butyl-4-( 3 '-nitrophenyl)-1.2,3,6-tetrahydropyrimidine-2one 4 G. of B-n-butylamino-m-nitropropiophenonehydrochloride preparedby the procedure of Part A were suspended in 10ml. of acetic acid and the suspension heated under relux for 0.5 hours.1.5 G. of potassium cyanate were added and, as usual, an exothermicreaction was noted. After cooling to room temperature 40 mls. water wereadded and the l-n-butyl-4-(3' nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one which precipitated out was collected byfiltration. This precipitate was extracted with hot methanol, and theinsoluble fraction crystallized from N,N-dimethylformamide to yield1-n-butyl-4-(3-nitrophenyl)-1,2,3,6- tetrahydropyrimidine-2-one with amelting point of 156 to 157C. Analysis of this product yielded thefollowing results:

C( H1 1 Found: 61.01 6.78 14.81 u HIT 2 Calculated: 61.07 6.22 15.26

EXAMPLE 14 Part A Part B l-Benzyl-4-( 3 -nitrophenyl 1 ,2,3,6-tetrahydropyrimidine-2-one.

5 G. of B-benzylamino-mmitropropiophenone hydrochloride prepared by theprocedure of Part A were suspended in 20 ml. of acetic acid and thesuspension hea ted under reflux for 0.5 hours. 1.5 G. of potassiumcyanate were added and, as usual, an exothermic reaction was noted.After cooling to room temperature 40 mls. water were added and the1-benzyl-4-(3'-nitrophenyl)- 1,2,3,6-tetrahydropyrimidine-Z-one whichprecipitated out was collected by filtration. This precipitate wasextracted with hot methanol, and the insoluble fraction crystallizedfrom N,N-dimethylformamide to yield 4 g. of the desired1-benzyl-4-(3-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-Z-one with amelting point of 168 to 170C. Analysis of this product yielded thefollowing results:

C(71) H( W Found: 6597 4.82 13.71 m is N11 :1

Calculated: 66.01 4.89 13.59

EXAMPLE 15 Part A B-(o-Hydroxyanilino)-3,4,S-trimethyoxypropiophenonehydrochloride G. of ,B-dimethylamino-3,4,5-trimethoxypropiophenonehydrochloride were added to 25 ml. of 50% aqueous, ethanol and stirringcontinued until all the phenone had dissolved. 2 g. of o-aminophenolwere added and the solution refluxed for 0.5 hours, then set aside tocool. Thereafter, the solution was extracted twicewith ml. ethylacetate, the' organic extracts combined and an excess (3 mls.)concentrated hydrochloric acid added to the organic phase. The solutionEXAMPLE 16 hydroacetone mixture, had a melting point of 1 12 to 1 C.

room temperature, 20 mls. water were added, and the l-2'-hydroxyphenyl)-4-(3"-bromophenyl)-1 ,2,3,6- tetrahydropyrimidineprecipitated out of solution. The suspension was extracted twice with 10mls. ethyl acetate. The organic extracts were combined andwashed.successively with 10% aqueous sodium hydroxide, 10% aqueous hydrochloricacid and water then dried over sodium sulfate, filtered and evaporatedto dryness. The residue was recrystallized from anN,N-dimethylformamide-ethyl acetate mixture to give the desired 1-(2-hydroxyphenyl )-4-( 3 ,4' ',5 -trimethoxyphenyll,2,3,6-tetrahydropyrimidine-2-one, which had a melting point of 224 to226C. Analysis of this product yielded the following results:

W H('7l) N0 Found: 63.94 5.79 8.02 m 20 2 5 Calculated: 64.03 5.56 7.86

Part B l-(2-Naphthyl )-4-( 3-nitrophenyl)-1,2,3,6-tetrahydropyrimidine2-one 2.5 G. of,8-(2-naphthylamino)-mnitropropiophenone hydrochloride prepared by theprocedure of Part A were dissolved in 10 ml. of acetic acid at 60C. 1.2G. of potassium cyanate were added and, as usual, an exothermic reactionwas noted. After cooling to room temperature, 20 mls. water were added,and the 1-(2'-hydroxyphenyl)-4-(3-bromophenyl)-1,2,3,6-tetrahydropyrimidine precipitated out of solution. Thesuspension was extracted twice with 10 mls. ethyl acetate. The organicextracts were combined and washed successively with 10% aqueous sodiumhydroxide, 10% aqueous hydrochloric acid and water then dried oversodium sulfate, filtered and evaporated to dryness. The residuewasrecrystallized from N,N-dimethylformamide to givethe desired1-(2-naphthyl)-4- (3 '-nitr0phenyl )-l ,2,3,6-tetrahydropyrimidine-2-one, which had a melting point of 250 to 253C.Analysis of this product yielded the following results:

C( H171) N0 Found: 69.39 4.46 12.38 C20 H16 N11 3 Calculated: 69.35 4.6512.13

EXAMPLE 17 H(7() NW?) Found: 70.45 5.25 9.03 C11 H16 NZ 3 Calculated:70.11 5.23 9.08

EXAMPLE 18 N( Found: 61.01 4.07 11.44 m H15 a 2 Calculated: 61.19 4.2811.61

EXAMPLE l91-(2-Propoxyphenyl)-4-(3'T-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one1 G. of 1-(2-hyrdoxyphenyl)-4-(3"-nitrophenyl)-.

1,2,3,6-tetrahydropyrimidine-3-one obtained by the procedure of Examplelhereinbefore was dissolved in 2 ml. pyridine and 2 ml. propionicanhydride were added to the solution. The reaction was conductedfollowing exactly the same procedure as in Example 17 to give1-(2-propoxyphenyl)-4-(3"-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one, whichwhen recrystallized from anN,N-dimethylformamide-ethanol mixture had a metlting point of 192 to193C. Analysis of this product yielded the following results:

Found: 62.39 4.86 11.68

m H17 u s Calculated: 62.11 4.66 11.44

EXAMPLE 2O 1-(2-Butyroxyphenyl)-4-( 3 "-nitrophenyl)-l,2,3,6-tetrahydropyrimidine-2-one l G. of1-(2-hydroxyphenyl)-4-(3"nitrophenyl)-1,'2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of ExampleI hereinbefore was dissolved in 2 m1. of pyridine and 2 ml. butyricanhydride were added to the solution. The reaction was conductedfollowing exactly the same procedure as in Example 17 to I give 1-(2-butyroxyphenyl)-4-( 3 '-nitrophenyl 1,2,3,6-tetrahydropyrimidine,which when recrystallized from an N,N-dimethylformamide-ethanol mixturehad a melting point of 178 to 180C. Analysis of this product yielded thefollowing results:

C(7() H(7() N(7r) Found: 63.12 5.23 11.20 C20 H19 NJ Calculated: 62.985.02 l 1.02

EXAMPLE 21 1-( 2 -Undecylenoxyphenyl )-4-( 3 -nitrophenyl 1,2,3,6-tetrahydropyrimidine-2 2 G. of1-(2-hydroxyphenyl)-4-(3"-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of Example1 hereinbefore were dissolved in 4 ml. pyridine and 2 ml. of undecenoylchloride were added to the solution. The reaction mixturewas allowed tostand at ambient temperature overnight. after which 5 ml. of water wereadded. The solution was extracted with ethyl acetate and the organicsolution washed successively with 10% aqueous sodium carbonate, water,10% aqueous hydrochloric acid and water, dried over sodium sulfate.filtered across silica gel and concentrated by heating in vacuo. Theconcentrated solution was set aside when crystals of 1-(2-undecylenoxyphenyl )-4-( 3 "-nitrophenyl 1,2,3,6-tetrahydropyrimidine-3-one separated out. This ester,recrystallized from ethyl acetate, had a melting point of 1 16 to C.Analysis of this product yielded the following results:

cwn H('/() NW) Found: 67.76 6.46 8.30 C27 H31 N11 5 Calculated: 67.906.54 8.81]

EXAMPLE 22 rahydropyrimidine-2-one 1 G. ofl-(2'-hydroxyphenyl)-4-(3"-nitrophenyl)-1,2,3.6-tetrahydropyrirnidine-Z-one obtained by the procedure of ExampleI hereinbefore was dissolved in 2 ml. pyridine and 1 ml. benzoylchloridewas added slowly to the solution. The reaction mixture was allowed tostand for 0.5 hours at roomtemperature after which 5 m1. of water wereadded and the reaction conducted following exactly the same procedure asin Ex ample 21 to give 1-(2-benzoxyphenyl)-4-(3"-nitropheny1)-1,2,3,6-tetrahydropyrimidine-2-one. This esterrecrystallized from ethyl acetate had a melting point of 205 to 206C.Analysis of thisproduct yielded the following results:

C(91) H(7r) Found: 66.69 4.33 23 11 s a Calculated: 66.49 4.12

EXAMPLE 23 1-( 2'-( 2-Ethylhexanolyoxy)-pheny1 )-4-( 3nitrophenyl)-1,2,3 ,6-tetrahydropyrimidine-2-one 1 G. of1-(2'-hydroxypheny1)-4-(3"-nitrophenyl)-l,2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of Example1 hereinbefore was dissolved in 2 ml. pyridine and 1 ml. ofZ-ethylhexanoyl chloride was added to the solution. The reaction mixturewas allowed to stand for 0.5 hours, after which 5 ml. water were addedand the reaction conducted following exactly the same procedure as inExample 21 to give the 2-ethylhexanoic ester of the starting material.This ester recrystallized from ethyl acetate hada melting point of 152to 153C. Analysis of this product yielded the following results:

(7rl H(7r) Found: 65.84 6.33 ct. H21 0.

Calculated: 65.88 6.22

product yieldedthe following results:

EXAMPLE 24 1-( 2-lsovaleroxyphenyl )-4-( 3 -nitrophenyl )-1 ,2,3,6-tetrahydropyrimidine-2-one 1 G. ofl-(2-hydroxyphenyl)-4-(3"-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of ExampleI hereinbefore was dissolved in 2 ml. pyridine and 1 ml. ofisovaleroylchloride was added to the solution. The reaction mixture wasallowed to stand for 0.5 hours after which 5 ml. water were added and 2ml. of a concentrated methanolic solution of barium hydroxide. Thesuspension was extracted with ethyl acetate and the organic solutiondried over sodium sulfate and filtered through silicagel. The filtratewas concentrated by heating in vacuo. The concentrated solution was setaside to cool when the desired 1-( 2 '-isovaleroxyphenyl )-4-( 3nitrophenyl)-l,2,3,6-tetrahydropyrimidine-Z-one precipitated out ofsolution. This ester had a melting point of 191 to 192C. Analysis ofthis product yielded thefollowing results:

Calculated:

EXAMPLE 25 1-(2'-ethoxycarboxyphenyl)-4-(3"-nitrophenyl)- l,2,3,-tetrahydropyrimidine-2-one l G. of1-(2'-hydroxyphenyl)-4-(3-nitrophenyl)1,2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of ExampleI hereinbefore was dissolved in 2 ml. pyridine and 1 ml. ofethylchloroforrnate was added slowly to the solution. The reactionmixture was allowed to stand at room temperature for 0.5 hours afterwhich water was added and the reaction con ducted following exactly theprocedure of Example 17 to give the ethylcarbonic ester of the startingmaterial. This ester had a melting point of 193 to 195C. Analysis ofthis product yielded the following results:

Found: 11.21

C19 H11 06 N3 Calculated: 59.52 4.41 11.44'

EXAMPLE 26 from N,N-dimethylformamide-ethyl acetate had a.

melting point of 222 to 223C. Analysis of this.

cw.) N171) Hm) Found: 61.05 4.38 I 11.73 IN 15 11 5 Calculated: 61.194.28 11.61

EXAMPLE 27 C(Vr) H1 N1 0 Found; 66.54 4.46 10.05 C211 H17 N3 05Calculated: 66.69 4.12 10.11

EXAMPLE 28 1-( 2-( 3 ,4, 5-trimethoxybenzoxy )-phenyl )-4-(4nitrophenyl)-1,2,3 ,6-tetrahydropyrimidine-2-one.

1 G. of 1-(2"-hydroxyphenyl)-4-(4"-nitrophenyl) l,-2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of ExampleShereinbefore was dissolved in 2 ml. pyridine and 0.8 g. of3,4,5-trimethoxybenzoylchloride was added to the solution. The reactionwas conducted following exactly the same procedure as in Example 21 togive the 3,4,5 trimethoxybe'nzoyl ester of the starting compound. Thisester had a melting point of 220 to 225C. Analysis of this productyielded the following results:

I C(7c1 H0 W Found: 61.69 4.73 8.73 C26 H23 N51 OR Calculated: 61.774.59 I 8.31

EXAMPLE 29 1-(2-Acetoxyphenyl)-4-(3"-bromophenyl)-12,3,6-tetrahydropyrimidine 2vone 1 G. ofl-(2'-hydroxyphenyl)-4-(3"-bromophenyl)-1,2,3,6-tetrahydropyrimidine-Z-one. obtained by the procedure of Example6 hereinbefore was dissolved in '2 ml. of pyridine and 2 ml. of aceticanhydride were added to the solution. The esterification reaction wasconducted following exactly the same procedure as in Example 17hereinbefore to give the desired l-(2- acetoxyphenyl )-4-( 3"-bromophenyl)-1,2,3 ,6-tetrahydropyrimidine'2-one. The compoundrecrystallized y from a mixture of N,N -dimethylformamide and ethylacetate had a melting point of 173 to 175C. Analysis of this productyielded the following results:

C(Vr) H( /r) N( 7r) BT07!) Found 55.62 4.24 7.00 20.55 ix is 'z aCalculated 55.83 3.91 7.23 20.63

EXAMPLE 30 l-(2'-Propoxyphenyl)-4-(3"-bromophenyl)-l,2,3,6-tetrahydropyrimidine-2-one l G. of1-(2-hydroxyphenyl)-4-(3-bromophenyl)-1,2,3,6-tetrahydropyrimidine-3-one obtained by the procedure of Example6 hereinbefore was dissolved in 2 ml. pyridine and 2 ml. propionicanhydride were added to the solution. The reaction was conductedfollowing exactly the same procedure as in Example 17 to give l-( 2-propoxyphenyl )-4-( 3 -bromophenyl 1,2,3,6-tetrahydropyrimidine-Z-one,which when recrystallized from an N,N-dimethylformamide-ethanol mixturehad a melting point of 182 to 185C. Analysis of this product yielded thefollowing results:

Found 56.74 4.01 .7.41 20.50 w n z a Calculated 56.87 4.27 6.98 19.92

EXAMPLE 31 l-( 2-( 3 ,4,5-Trimethoxy )-benzoxy )-4'( 3 bromophenyl-l,2,3,6-tetrahydropyrimidine-Z-one l G. ofl-(2-hydroxyphenyl)-4-(4"-bromophenyl)-l,2,3,6-tetrahydropyrimidine-2-one obtained by the procedure of Example6 hereinbefore was dissolved in 2 ml. pyridine and 0.8 g. of2,3,5-trimethoxybenzoylchloride was added to the solution. The reactionwas conducted following exactly the same procedure as in Example 21 togive the 3,4,5-trimethoxybenzoyl ester of the starting compound. Thisester. recrystallized from an N,N-dimethylformamide-ethyl acetatemixture. had a melting point of 197 to 198C. Analysis of this productyielded the following results:

C(7r) H(71) NW1) Br(71) Found 57.65 4.38 5.05 15.04 26 2I1 2 GCalculated 57.89 4.30 5.19 14.82

EXAMPLE 32 l-( 2-ethoxycarboxyphenyl )-4-( 3 -bromopheny1)-1,2,3,6-tetrahydropyrimidine-2-one l G. of1-(2'-hydroxyphenyl)-4-(3-bromophenyl)-l,2,3,-tetrahyclropyrimidine-2-one obtained by the procedure of Example6 hereinbefore was dissolved in 2 ml. pyridine and 1 ml. ofethylchloroformate was added dropwise to the solution. The reactionmixture was allowed to stand at room temperature-for 0.5 hours afterwhich-water was added and the reaction con I results:

C1 7!) N('7r) Hm) 'BrlVzl Found 54.61 6.66 4.21 19.50

c u omaar Calculated 54.69 6.71 4.11 19.15

EXAMPLE 33 l-( 2-Acetoxyphenyl)-4-( 3 -chlorophenyl )-1 2,3,6-tetrahydropyrimidine-2-one 1 G. of 1-(2l-hydroxyphenyl)-4-(3f-chloropheny1).- 1,2,3,6-tetrahydropyrimidine-2-one prepared by theprocedure of Example 7 hereinbefore was dissolvedin 2 ml. of pyridineand 2 ml. of acetic anhydride were added to the solution. The reactionmixture was allowed to stand for 1 hour at ambient temperature (25C.),then 5 ml. water were added when the desired 1-( 2'-acetoxyphenyl -4-( 3'-chlorophenyl )-1 ,2,3,6 slowly precipitated out of solution in theform of crystals. The ester, recrystallized from benzone, had a meltingpoint of 152 to 154C. Analysis of this product yielded the followingresults:

cw.) 11w.) N('7r) Cl(71) Found 63.25 4.58 8.27 10.60

c n w o ci Calculated 63.06 4.43 8.18 10.34

EXAMPLE 34 1-( 2'-Acetoxyphenyl)-4 3 -iodophenyl 1 .2,3,6-tetrahydro-2-one g 1 G. of l-(2'-hydroxyphenyl)-4-(3-iodophenyl)-1,2,3,o-tetrahydropyrimidine-2-one prepared by the procedure of Example8 hereinbefore was dissolved in 2 ml. of pyridine and 2 ml. of aceticanhydride were added to the solution. The reaction mixture was al-' Hut)N1 2) 11%) 0%) Found 50.01 3.51 6.31 29.02 cmusw oa Calculated 49.793.48 6.45 29.22

EXAMPLE 35 1-(2'-Propoxyphenyl )-4-( 3"-iodophenyl)-1,2,3,6-tetrahydropyrimidine-2-one 1 G. of1-(2-hydroxyphenyl)-4-(3"-iodophenyl)- l,2,3,6tetrahydropyrimidine-3-oneobtained by the procedure of Example 8 hereinbe fore was dissolved in 2ml. pyridine and 2 ml. propionic anhydride were added to the solution.The reaction was conducted following exactly the same procedure as'inExample 17 to give l-(2'-propo'xyphenyl)-4-( 3-iodophenyl)- 1 2,3,6-

tetrahydropyrimidine-Z-one, which when recrystallized.

from ethyl acetate had a melting point of 192 to 194C. Analysis of thisproduct yielded the following results:

C(Vc) H(%) Found: 50.40 3.94 m 11 2 n Calculated: 50.68 4.25

EXAMPLE 36 Found: 4.16

' Calculated 60.64 4.01 7.45

Such methods of manufacture as have been described in the foregoingspecific examples'can, of course, be readily modified by one skilled inthe art to produce any of the novel compounds encompassed by Formula l.

' EXAMPLE 37 Tablets having the following composition'were made upaccording to the procedure described below:

Formulation Ingredient Content 1-(2'-Hydroxyphenyl)-4-(3"ni trophenyl)-l2,3.fi-tetrahydropyrimidinegrams 2-one 175 Lactose 502.25 Starch 122Dextrin Solution) q.s. Stearic acid 3.5 Magnesium stearate 1.75

Procedure The tetrahydropyrimidine, lactose and starch were dried andpassed through a sieve of aperture size 420p" This mixture was thengranulated with the 20% dextrin solution, sifted at aperture size 700p,air-dried at room temperature overnight, and again sifted at aperturesize 700g. The dried granules were thoroughly mixed with IngredientContent l-Adamantyl-4-(3'-nitrophenyl)-l 2.3.6

tetrahydropyrimidine-Z-one 5 mg.

Lactose 145 mg.

Procedure I The l-adamantyl-4-(3'-nitrophenyl)-l,2,3,6-tetrahydropyrimidine-2-one and the lactose were passed throug aUS. No. 40 mesh sieve, mixed well together and filled into gelatincapsules so that each contained 150 mg. of mixed powder.

In the foregoing Examples 37 and 38, the 1-(2- hydroxyphenyl )-4-( 3mitrophenyl )-1 ,2,3 ,6-tetrahydropyrimidine-2-one and l-adamantyl-4-( 3nitrophenyl )-l ,2,3,6-tetrahydropyrimidine-Z-one may 1 be wholly orpartly replaced by another pharmacologically active compound of theinvention.

The effectiveness and toxicity of typical compounds of this inventionwere determined by standard pharmacological tests usedinneuropharmacological evaluation, such as observation of generalawareness and mood, behaviour, reflexes, locomotion, posture, muscletone, etc., of the experimental animals.

While the foregoing description refers to the preparation of certainillustrative tetrahydropyrimidine compounds and certain illustrativepharmaceutical compositions suitable for administering the novelcompounds the stearic acid and magnesium stearate as lubricating agentsand thereafter compressed into 230 mg. scored tablets (each containing50 mg. of the tetrahydro-- pyrimidine compound) on a suitabletablett'ing die.

EXAMPLE 38 in therapeutic applications it will be understood that theinvention is not to be limited thereto and that numerous modificationsand variations may be made without departing from the spirit of theinvention. It is also to be understood that the following claims areintended to cover all the generic and specific features of the inventionwhich, as a matter of language, might be said to fall therebetween.

Having described ourinvention, what we claim as new and desire tosecure-by Letters Patent is:

1. A 1,2,3,6-tetrahydropyrimidine 2-one compound Pfl f a a wherein X isinthe 3- or 4-position and is selected from the group consisting of H,N0 CE, and halogen, and wherein R is selected from'the groupconsistingof alkylhaving l to 7 carbon atoms, phenyl. and 3,4,5-trimethoxyphenyl.

2. A compound as claimed in claim 1 which is 1-(2- -l.li:ni ro lte llr1.2 .559952%...

Capsules each having the following composition weredropyrirriidifi-lone.

made up according to the procedure described below.

Formulation 3. A compound as claimed in claim 1 which is 1-(2-benzoyloxyphenyl )-4-( 3 -nitrophenyl l ,2,3,6-tetrahydropyrimidine-2-one.

of the formula:

7 27 2s 4. A compound as claimed in claim 1 which is 1-(2'- I A u v A A1 acetoxyphenyl )-4-( 3 -bromophenyl )-l ,2,3 ,6-tetrahy- 1;dropyrimidine-2-one. r 5. A l,2,3,6-tetrahydropyrimidine-2-one compoundNE of the formula:

1O M 011 U T' wherein n is one, wherein R is in the 3-position and is NHselected from the group consisting of NO and halogen, and wherein R islower alkyl having 1 to 5 carbon atoms, Ladamantyl, Z-naphthyl, amonocyclic alkyl having 3 to 8 carbon atoms, bicyclo-[3.l.()]-hexane,bicy- 4 clo-[2.2.l]-heptane, and phenyl-lower alkyl, wherein the loweralkyl has 1 to 5 carbon atoms.

7. A compound as claimed in claim 6 which isladamantyl-4(3'-nitrophenyl)-1,2,3,6-tetrahywherein X is in the 3- or4-position and is selected from d i idi zthe group Consisting of H, 2CF13 and halogen 8. 1-(2'-ethoxycarboxyphenyl)-4-(3"-nitrophenyl)- 6. Al,2,3,6-tetrahydropyrimidine-2-one compound 1,23,6 tetrahydmpyrimidine-Z-one.

2. A compound as claimed in claim 1 which is1-(2''-acetoxyphenyl)-4-(3''''-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one.3. A compound as claimed in claim 1 which is1-(2''-benzoyloxyphenyl)-4-(3''''-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one.
 4. A compound as claimed in claim 1 which is1-(2''-acetoxyphenyl)-4-(3''''-bromophenyl)-1,2,3,6-tetrahydropyrimidine-2-one.5. A 1,2,3,6-tetrahydropyrimidine-2-one compound of the formula:
 6. A1,2,3,6-tetrahydropyrimidine-2-one compound of the formula:
 7. Acompound as claimed in claim 6 which is1-adamantyl-4-(3''-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one. 8.1-(2''-ethoxycarboxyphenyl)-4-(3''''-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one.